Progesterone and the oligodendroglial lineage:: Stage-dependent biosynthesis and metabolism
Progesterone and the oligodendroglial lineage:: Stage-dependent biosynthesis and metabolism
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DOI：
10.1002/glia.1117
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发表时间：
2001-12-01
期刊：
影响因子：
6.2
通讯作者：
Schumacher, M
中科院分区：
文献类型：
--
作者：
Gago, N;Akwa, Y;Schumacher, M
已有证据表明，神经类固醇，特别是孕激素（PROG）及其代谢物，可能参与周围神经系统的髓鞘形成和再髓鞘形成，但在中枢神经系统（CNS）的研究很少。这项工作的目的是研究PROG在少突胶质细胞谱系的三个重要阶段的合成和代谢能力：少突胶质细胞前祖细胞（OPP），少突胶质细胞祖细胞（OP）和完全分化的少突胶质细胞（OL）。实验已经在体外使用高纯度的大鼠脑原代细胞培养物进行。将细胞与PROG的直接前体h- 3-孕烯醇酮（H-3-PREG）或H-3-PROG孵育，然后用薄层色谱和高效液相色谱（HPLC）鉴定类固醇代谢物。采用逆转录-聚合酶链反应（RT-PCR）检测关键甾体生成酶mRNA的表达。结果表明，只有OPP和OP表达3 β -羟基类固醇脱氢酶/Delta5-Delta4异构酶mRNA，而OL不表达，并能从PREG合成PROG。在研究的三种细胞类型中，PROG被5 α -还原酶的1型异构体代谢为5 α -二氢孕酮（5 α -DHPROG）。该酶在OL中的活性比在OPP和op中的活性高5倍。5 α -DHPROG进一步转化为3 α，5 α -四氢孕酮（3 α,5 α -THPROG），被称为GABAA受体的正变构调节剂，或转化为3 β -异构体。OPP中3 - α，5 - α -THPROG的合成比其他细胞高10倍，而3 - α，5 - α -THPROG的产生不随细胞分化而改变。在少突胶质细胞分化过程中观察到的PROG合成和代谢以及神经甾体生成的剧烈变化可能有助于少突胶质细胞的发育或髓鞘形成过程。(C) 2001 Wiley-Liss, Inc。
Evidence has been accumulated showing that neurosteroids, particularly progesterone (PROG) and its metabolites, may participate in myelination and remyelination in the peripheral nervous system, but very few studies have been undertaken in the central nervous system (CNS). The aim of this work was to investigate the capacities of synthesis and metabolism of PROG at three important stages of the oligodendroglial lineage: oligodendrocyte pre-progenitors (OPP), oligodendrocyte progenitors (OP), and fully differentiated oligodendrocytes (OL). Experiments have been conducted in vitro using highly purified primary cell cultures from rat brain. Cells were incubated With H-3-pregnenolone (H-3-PREG), the immediate precursor of PROG, or with H-3-PROG, and steroids metabolites were then identified by thin layer chromatography and high-performance liquid chromatography (HPLC). mRNA expression of key steroidogenic enzymes was evaluated by reverse transcription-polymerase chain reaction (RT-PCR). The results showed that only OPP and OP, but not OL, expressed 3 beta -hydroxysteroid dehydrogenase/Delta5-Delta4 isomerase mRNA and were able to synthesize PROG from PREG. In the three cell types studied, PROG was metabolized by the type 1 isoform of 5 alpha -reductase into 5 alpha -dihydroprogesterone (5 alpha -DHPROG). This enzyme exhibited a 5-fold higher activity in OL than in OPP and OP. 5 alpha -DHPROG was further transformed either into 3 alpha ,5 alpha -tetrahydroprogesterone (3 alpha ,5 alpha -THPROG), known as a positive allosteric modulator of the GABAA receptor, or into the 3 beta -isomer. The 3 alpha ,5 alpha -THPROG synthesis was 10 times higher in OPP than in the other cell studied, while the 3 beta ,5 alpha -THPROG production did not change with cell differentiation. PROG synthesis and metabolism and the dramatic changes in neurosteroidogenesis observed during the oligodendroglial differentiation may contribute to oligodendrocyte development or the myelination process. (C) 2001 Wiley-Liss, Inc.